Chronic kidney disease (CKD) represents a major public health problem in developed and developing countries. It is estimated that approximately 5% of the adult U.S. population is affected by CKD, which is defined as serum creatinine concentrations greater than 1.2 to 1.5 mg/dL [1]. The European Kidney Health Alliance (EKHA) reports that approximately 10% of European citizens are affected by some degree of CKD [2].

CKD and end-stage renal disease (ESRD) are associated with an increased risk of mortality, increased rate of hospitalisation, and decreased life expectancy [3]. Progression from early to late stages of CKD generally results in the onset of new symptoms and concomitant complications. Frequent complications and comorbidities of CKD include fluid and electrolyte abnormalities, anaemia, secondary hyperparathyroidism and renal osteodystrophy, hypertension and hyperlipidaemia, metabolic acidosis, and several other comorbidities involving malnutrition, pruritus and uremic bleeding. CKD patients are at increased risk of cardiovascular disease (CVD), which includes coronary heart disease (CHD), cerebrovascular disease, peripheral vascular disease, and heart failure. The management of underlying and evident comorbidities (either as causes or consequences of CKD) and the prevention or delay of its progression to ESRD are complex.

In ESRD patients, the initiation of renal replacement therapies (RRTs), such as long-term dialysis (including haemodialysis (HD) or peritoneal dialysis (PD)) or transplantation, is usually indicated to relieve uremic symptoms and detoxify, whereas kidney transplantation (cadaveric or living donor transplantation) is the therapy of choice for ESRD [4].

Multidisciplinary health care teams of physicians, nurses, dieticians, and clinical pharmacists share the goal of preventing disease progression and managing comorbid conditions in CKD and ESRD patients. As specialists in pharmacotherapy, clinical pharmacists are routinely involved in patient care and interact with other health care professionals, addressing multiple, often unmet needs for pharmacotherapy optimisation. Ideally, this happens through a preventive, rather than a reactive, approach. Evidence from the literature supports the involvement of clinical pharmacists in several disease areas and underlines the positive patient outcomes and improvement of care that result [5, 6].

The medical management of predialysis and dialysis patients involves complex and highly variable pharmacotherapy, including frequent monitoring and evaluation to ensure optimal pharmacotherapy, adherence to medication, and control of comorbidities and other risk factors. A high number of prescribed medications, poor medication adherence, and frequent dosage changes may contribute to drug-related morbidity and related problems [7]. Several studies report poor quality and gaps in the care of CKD patients with respect to the treatment of comorbidities, referrals to specialists, and the preparation for RRTs [8, 9].

Clinical pharmacists are directly engaged in the care of CKD and ESRD patients in different settings. Various possibilities and opportunities for clinical pharmacists to contribute to this field are described and exemplarily supported by evidence in an American College of Clinical Pharmacy (ACCP) opinion paper [10].

This literature review aims to systematically summarise the published evidence on the role of clinical pharmacists in the care of CKD and ESRD patients across different settings, to synthesise and highlight findings on the impact of clinical pharmacists, their various key activities, and their main areas of involvement, and to describe the different characteristics of clinical pharmacy services for the CKD and ESRD patient population.

A literature search was conducted using the Medline (1970 - Week 46, 2010), Embase (1996 - Week 45, 2010) and International Pharmaceutical Abstracts (IPA) (1970 - Oct 2010) databases to identify relevant articles. In Medline, the following combinations of Medline Medical Subject Headings (Mesh) terms were used as our search strategy: ("pharmacy service, hospital" OR "pharmacists" OR "pharmaceutical services") AND ("renal insufficiency" OR "kidney" OR "renal replacement therapy"). In Embase and IPA, the search strategy combined the terms ("clinical pharmacy" OR "pharmaceutical care" OR "pharmacist" OR "hospital pharmacy") AND ("renal insufficiency" OR "kidney" OR "renal replacement therapy"). The references sections of the returned publications and review articles were further screened for additional hits. Data were extracted and reviewed by the first study author (GS) and independently reviewed by the second author (RLG). Discrepancies were solved by discussion among the study authors.

Predefined data parameters (namely, the study design, duration and setting, the number of included patients, the types of interventions, the relevant outcomes, the results, and available statistical values) were extracted from the literature, summarised in an Excel spreadsheet, and reviewed.

The initial Medline, Embase and IPA searches yielded 339, 199, and 323 citations, respectively. The detailed search results are described in Figure 1.

A total of 861 citations were initially screened for inclusion criteria, and after removing duplicates, a total of 21 citations remained for full review and analysis. The predominant reason for exclusion was a lack of interventional and/or assessable data. Several initial citations had to be excluded because they provided data only on the impact of screening on appropriate renal dosing, with or without computerised support, or they provided only economic data.

Our systematic review synthesises evidence on the impact of clinical pharmacist involvement in DRPs in general, with respect to different comorbidities (e.g., anaemia and lipid management), and regarding educational issues in CKD and ESRD patients.

Evidence of gaps in the care of patients with renal impairment (e.g., poor hypertension control, anaemia control in CKD and dialysis patients) is published in the literature [8, 9]. For the patient's sake, these gaps must be addressed using all available methods. Enhancing the involvement of clinical pharmacists may be one potential strategy. Thus, for example, clinical pharmacist-led programmes showed higher proportions of CKD patients achieving haemoglobin target [25], increased medication knowledge [32], decreased hospitalisation rates [22], and an overall improvement in the quality of life of dialysis patients [23].

By addressing the issues illustrated in Table 4 in their general and more specified clinical work, clinical pharmacists fulfil the requirements stated in the NKF-KDOQI Guidelines "Chronic Kidney Disease: Evaluation, Classification and Stratification" [35], which explicitly highlight the need for regular medication reviews, including dosage adjustment, adverse drug event (ADE) detection, drug interaction detection, and therapeutic drug monitoring (TDM). Given the nature of their major responsibilities and tasks, clinical pharmacists interact with patients, physicians, and other health professionals and share the goal of optimising pharmacotherapy and patient care. This multidisciplinary and multilevel approach is underlined by all included studies. Clinical pharmacists, as pharmacotherapy experts, are engaged in the care of the CKD and ESRD patient population at different stages. Potential responsibilities of clinical pharmacists may comprise attainment of blood pressure, glycaemic, and lipid goals, and the early evaluation and treatment for proteinuria, anaemia, and secondary hyperparathyroidism, among others [10]. Optimal control of hyperglycaemia, including maximal suppression of urinary albumin excretion by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in diabetic patients with persistent microalbuminuria, and hypertension can limit progression of CKD to ESRD. Evidence of improved glycaemic and blood pressure control and decreased levels of microalbuminuria through clinical pharmacists' involvement in patient care is published [36–38]. However, due to our search strategy, studies explicitly addressing only these latter aspects are not included in this systematic review. Furthermore, no study of clinical pharmacy services in CKD patients investigating the slowing down of disease progression could be identified.

The CKD and ESRD population can be characterised by its vulnerability and susceptibility to drug-therapy-related morbidity due to many factors. Commonly reported DRPs in CKD or ESRD patients (e.g., dosing problems and medical record discrepancies) are not surprising given the complexity of dosing during either type of renal replacement therapy due to common changes in drug pharmacodynamics and pharmacokinetics [39]. This fact is further aggravated by the high number of concomitant drugs used and comorbidities, as studies report an average number of 10 to 12 drugs per day and five comorbidities for HD patients [7]. Intensified care and additional monitoring are warranted for patients taking more than five drugs, patients with more than 12 total medication doses, patients with drug regimens prone to frequent changes and three or more concurrent disease states, and patients with a history of non-compliance, and the presence of drugs requiring TDM [40]. CKD and HD patients generally fulfil all of these criteria and therefore warrant increased monitoring. Problems with medical record discrepancies and the accuracy of medication profiles, which are among the most commonly reported DRPs, are further highlighted in a prospective observational study of 63 HD patients, which reports record discrepancies in 60% of all patients. Several clinical pharmacy studies provide insights into the risk factors for DRPs. One study [15] highlights an inverse correlation between residual kidney function (based on creatinine clearance) and the number of DRPs. Another study reports a positive correlation between the number of DRPs, on the one hand, and age and length of time on dialysis, on the other [21]. All of these aspects present opportunities for clinical pharmacist to engage in CKD and ESRD patient care.

Generally, more than three-quarters of clinical pharmacist interventions and suggestions were accepted by physicians. This physician acceptance rate is well within the range of other reported acceptance rates based on a review of clinical pharmacist impact on DRPs and clinical outcomes [6]. Due to the use of different classification systems and the resulting heterogeneity of DRPs, a profound statistical analysis was not performed.

No studies could be identified that explicitly addressed the issue of adherence in CKD or ESRD patients; nonetheless, it presents a major barrier to optimal patient care. Especially among patients taking a high number of prescription drugs, complex medication schemes and long treatment periods cause adherence to wane [41]. Guaranteeing a high level of medication knowledge may be one strategy to increase adherence and to prevent DRPs resulting from incorrect drug use or overall failure to take medications. Clinical pharmacist intervention to improve patient medication knowledge was the study objective in two of the included studies [31, 32], which could be achieved.

We identified a higher proportion of studies investigating disease-oriented versus patient-oriented outcomes. Patient-oriented outcomes are those that directly matter to patients, that is, those regarding longer life and improved quality of life. From an evidence-based point of view, studies investigating patient-oriented outcomes contribute more to the overall evidence and therefore have to be weighted more heavily. However, further studies with hard endpoints, as highlighted in Table 5 as well as longer study periods are definitely warranted, as they provide further evidence on the role of pharmacists in the care of CKD and ESRD patients and other patient groups.

Several studies on clinical pharmacist involvement were identified by our search strategy, but only four of them were controlled trials (two by the same authors) with high-quality methodological design and therefore a higher evidence impact. We decided to also include abstracts in our review, because we are convinced that these small studies of the impact of clinical pharmacy on patient care contribute to the overall evidence on this topic. We could not identify any studies that specifically addressed PD patients. However, in the two studies that included PD patients, the authors did not comment on any special issues (e.g., regarding the type of DRPs or adherence). Given the complexity and specifics of drug dosing during PD, the high need for education and patient training, and the high risk of infections (e.g., peritonitis), data specific to this patient population would be interesting and warranted. We hypothesise that clinical pharmacists are routinely integrated into different aspects of PD patient care, but due to irregular clinical attachment (as compared to HD patients, who generally attend clinic three times per week), such studies are more difficult to perform.

Furthermore, regarding CKD patient studies, it was not possible to subdivide different clinical pharmacist activities and further relevant findings (e.g., common DRPs and performed interventions) according to CKD stage.

Our review is subject to publication bias. We could not identify any studies showing that clinical pharmacy interventions had a negative impact on patient care. Furthermore, studies that used DRPs and physician acceptance rates as outcome parameters lacked information about rejected interventions and the reasons for rejection. The reporting of clinical significance assessments for performed interventions increases the scientific value of clinical pharmacy research, primarily by reducing bias. Data on the impact of clinical pharmacists on hospitalised inpatients is also scarce. In addition, the majority of the studies were published in the United States. Interestingly, only one study [31] from Europe could be identified; three of the remaining four studies were from Asia [14, 28, 32], and one was from New Zealand [21]. However, we hypothesise that clinical pharmacists are widely engaged in the care of CKD and ESRD patients. There are, for example, special interest groups dedicated to their care, such as the United Kingdom Renal Pharmacist Group [42]. Further high-quality studies on the impact of clinical pharmacists on key issues such as adherence and disease progression are thus warranted.

All identified studies on the involvement of clinical pharmacists in the care of CKD and ESRD patients showed some benefit. However, high-quality evidence on the impact of clinical pharmacy services is limited to a few studies. Clinical pharmacists address areas requiring improvement as well as unmet DRPs responsively and preventatively. By doing so, clinical pharmacists positively contribute to the care of patients with impaired renal function and reduce the gaps in current patient care.